20 results on '"Blanco-Heredia J"'
Search Results
2. 1246P Detection of alternative lengthening of telomeres (ALT) across cancer types based on tumor-normal multigene panel sequencing
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Blanco Heredia, J., Diplas, B.H., El Nahhas, O.S.M., Selenica, P., Pareja, F., Mandelker, D., Weigelt, B., Riaz, N., Rosen, E., Sfeir, A., and Reis-Filho, J.S.
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- 2023
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3. 2341P Novel therapeutic opportunities in metaplastic breast cancer
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Pareja, F., Gazzo, A., Dopeso, H., Brown, D., Selenica, P., Zhu, Y., Blanco Heredia, J., Gusain, L., Pei, X., Marra, A., Montagna, G., Abuhadra, N., Wen, H., Brogi, E., Riaz, N., Chandarlapaty, S., Scaltriti, M., Powell, S., Weigelt, B., and Reis-Filho, J.S.
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- 2023
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4. 33P Immune analysis of lymph nodes in relation to the presence or absence of tumour infiltrating lymphocytes in triple negative breast cancers
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Quintana, A., primary, Peg, V., additional, Moline, T., additional, Prat, A., additional, Paré, L., additional, Galván, P., additional, Villacampa, G., additional, Dientsmann, R., additional, Perez, J., additional, Muñoz, E., additional, Martí, M., additional, Blanco-Heredia, J., additional, Dos Anjos, C., additional, Vazquez, M., additional, de Mattos, L., additional, and Cortés, J., additional
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- 2020
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5. Immune Correlates of HIV Control
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Prado, J.G., primary, Carrillo, J., additional, Blanco-Heredia, J., additional, and Brander, C., additional
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- 2011
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6. Unique features of HLA-mediated HIV evolution in a Mexican cohort: a comparative study
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Brumme Zabrina L, Heckerman David, Garcia-Morales Claudia, Garrido-Rodriguez Daniela, Blanco-Heredia Juan, Valenzuela-Ponce Humberto, Carlson Jonathan M, Ormsby Christopher E, Avila-Rios Santiago, Mallal Simon, John Mina, Espinosa Enrique, and Reyes-Teran Gustavo
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level. However, it is not known whether characteristic HLA frequency distributions in different populations have resulted in additional unique footprints. Methods The phylogenetic dependency network model was applied to assess HLA-mediated evolution in datasets of HIV pol sequences from free plasma viruses and peripheral blood mononuclear cell (PBMC)-integrated proviruses in an immunogenetically unique cohort of Mexican individuals. Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA. Results Forty three different HLA-HIV codon associations representing 30 HLA-HIV codon pairs were observed in the Mexican cohort (q < 0.2). Strikingly, 23 (53%) of these associations differed from those observed in the well-powered IHAC cohort, strongly suggesting the existence of unique characteristics in HLA-mediated HIV evolution in the Mexican cohort. Furthermore, 17 of the 23 novel associations involved HLA alleles whose frequencies were not significantly different from those in IHAC, suggesting that their detection was not due to increased statistical power but to differences in patterns of epitope targeting. Interestingly, the consensus differed in four positions between the two cohorts and three of these positions could be explained by HLA-associated selection. Additionally, different HLA-HIV codon associations were seen when comparing HLA-mediated selection in plasma viruses and PBMC archived proviruses at the population level, with a significantly lower number of associations in the proviral dataset. Conclusion Our data support universal HLA-mediated HIV evolution at the population level, resulting in detectable HLA-associated footprints in the circulating virus. However, it also strongly suggests that unique genetic backgrounds in different HIV-infected populations may influence HIV evolution in a particular direction as particular HLA-HIV codon associations are determined by specific HLA frequency distributions. Our analysis also suggests a dynamic HLA-associated evolution in HIV with fewer HLA-HIV codon associations observed in the proviral compartment, which is likely enriched in early archived HIV sequences, compared to the plasma virus compartment. These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.
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- 2009
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7. The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
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Daniel Guimarães Tiezzi, Juan Blanco-Heredia, Guillermo Villacampa, Paolo Nuciforo, Carlos Caldas, Rodrigo Dienstmann, Patricia Villagrasa, Pol Cusco, Carla A. Souza, Suet-Feung Chin, Roberta Fasani, Isabel T. Rubio, Aleix Prat, Vanesa Ortega, Javier Cortes, Samuel Gonçalves-Ribeiro, Leticia De Mattos-Arruda, Laia Paré, Stephen John Sammut, Jose Perez-Garcia, De Mattos-Arruda, Leticia [0000-0002-4992-3645], Cortes, Javier [0000-0001-7623-1583], Tiezzi, Daniel G [0000-0002-2660-0093], Gonçalves-Ribeiro, Samuel [0000-0002-0261-3965], Chin, Suet-Feung [0000-0001-5697-1082], Prat, Aleix [0000-0003-2377-540X], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Tiezzi, Daniel G. [0000-0002-2660-0093], Institut Català de la Salut, [De Mattos-Arruda L] IrsiCaixa, Germans Trias i Pujol University Hospital, Badalona, Spain. Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain. Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK. [Cortes J] Oncology Department International Breast Cancer Center (IBCC), Quiron Group, Barcelona, Spain. Medica Scientia Innovation Research (MedSIR), Barcelona, Spain. Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA. Breast Cancer Research program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain. [Blanco-Heredia J] IrsiCaixa, Germans Trias i Pujol University Hospital, Badalona, Spain. Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain. [Tiezzi DG] Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK. Breast Disease Division, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil. [Villacampa G, Gonçalves-Ribeiro S, Cusco P, Fasani R, Dienstmann R, Nuciforo P, Rubio IT] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ortega V] Breast Cancer Research program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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0301 basic medicine ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,medicine.medical_treatment ,32 Biomedical and Clinical Sciences ,medicine.disease_cause ,Càncer - Aspectes genètics ,631/67/1857 ,Tumour biomarkers ,chemistry.chemical_compound ,0302 clinical medicine ,Cancer genomics ,2.1 Biological and endogenous factors ,Pharmacology (medical) ,Otros calificadores::/terapia [Otros calificadores] ,Neoadjuvant therapy ,RC254-282 ,Cancer ,2 Aetiology ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Mutation ,article ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3 Good Health and Well Being ,HORMÔNIOS ,3204 Immunology ,Therapeutics::Combined Modality Therapy::Neoadjuvant Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Oncology ,030220 oncology & carcinogenesis ,Eribulin ,Stromal cell ,Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES] ,631/67/69 ,03 medical and health sciences ,Immune system ,Breast cancer ,Downregulation and upregulation ,Breast Cancer ,medicine ,Genetics ,Radiology, Nuclear Medicine and imaging ,Epithelial–mesenchymal transition ,fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS] ,business.industry ,Other subheadings::/therapy [Other subheadings] ,631/67/1347 ,medicine.disease ,3211 Oncology and Carcinogenesis ,030104 developmental biology ,chemistry ,FOS: Biological sciences ,Mama - Càncer - Tractament ,Cancer research ,terapéutica::tratamiento combinado::tratamiento neoadyuvante [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,business - Abstract
The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p
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- 2021
8. Chromothripsis-mediated small cell lung carcinoma.
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Rekhtman N, Tischfield SE, Febres-Aldana CA, Lee JJ, Chang JC, Herzberg BO, Selenica P, Woo HJ, Vanderbilt CM, Yang SR, Xu F, Bowman AS, da Silva EM, Noronha AM, Mandelker DL, Mehine M, Mukherjee S, Blanco-Heredia J, Orgera JJ, Nanjangud GJ, Baine MK, Aly RG, Sauter JL, Travis WD, Savari O, Moreira AL, Falcon CJ, Bodd FM, Wilson CE, Sienty JV, Manoj P, Sridhar H, Wang L, Choudhury NJ, Offin M, Yu HA, Quintanal-Villalonga A, Berger MF, Ladanyi M, Donoghue MTA, Reis-Filho JS, and Rudin CM
- Abstract
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis - massive, localized chromosome shattering - recurrently involving chromosomes 11 or 12, and resulting in extrachromosomal (ecDNA) amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.
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- 2024
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9. APOBEC3 mutagenesis drives therapy resistance in breast cancer.
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Gupta A, Gazzo A, Selenica P, Safonov A, Pareja F, da Silva EM, Brown DN, Zhu Y, Patel J, Blanco-Heredia J, Stefanovska B, Carpenter MA, Pei X, Frosina D, Jungbluth AA, Ladanyi M, Curigliano G, Weigelt B, Riaz N, Powell SN, Razavi P, Harris RS, Reis-Filho JS, Marra A, and Chandarlapaty S
- Abstract
Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer
1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.- Published
- 2024
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10. Converging and evolving immuno-genomic routes toward immune escape in breast cancer.
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Blanco-Heredia J, Souza CA, Trincado JL, Gonzalez-Cao M, Gonçalves-Ribeiro S, Gil SR, Pravdyvets D, Cedeño S, Callari M, Marra A, Gazzo AM, Weigelt B, Pareja F, Vougiouklakis T, Jungbluth AA, Rosell R, Brander C, Tresserra F, Reis-Filho JS, Tiezzi DG, de la Iglesia N, Heyn H, and De Mattos-Arruda L
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- Humans, Female, Genomics methods, Tumor Microenvironment, Breast Neoplasms genetics, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions., (© 2024. The Author(s).)
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- 2024
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11. Virus-like particle-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice.
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Barajas A, Amengual-Rigo P, Pons-Grífols A, Ortiz R, Gracia Carmona O, Urrea V, de la Iglesia N, Blanco-Heredia J, Anjos-Souza C, Varela I, Trinité B, Tarrés-Freixas F, Rovirosa C, Lepore R, Vázquez M, de Mattos-Arruda L, Valencia A, Clotet B, Aguilar-Gurrieri C, Guallar V, Carrillo J, and Blanco J
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- Humans, Animals, Mice, Antigens, Neoplasm metabolism, Peptides, Receptors, Antigen, T-Cell metabolism, Immunotherapy methods, Neoplasms genetics, Vaccines, Cancer Vaccines
- Abstract
Background: Neoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in-silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. Moreover, the therapeutic potential of neoantigen-based vaccines may be enhanced using an optimal delivery platform that elicits robust de novo immune responses., Methods: We developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction, as well as the interaction between the peptide/MHC-I complex and the TCR, in its prediction strategy. Moreover, to maximize neoantigens' therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance., Results: We generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments., Conclusions: Our results indicate the relevance of incorporating other immunogenic determinants beyond the binding of neoantigens to MHC-I. Thus, neoVLPs loaded with neoantigens enhancing the interaction with the TCR can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy., (© 2024. The Author(s).)
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- 2024
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12. Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma.
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Mandelker D, Marra A, Zheng-Lin B, Selenica P, Blanco-Heredia J, Zhu Y, Gazzo A, Wong D, Yelskaya Z, Rai V, Somar J, Ostafi S, Mehta N, Yang C, Li Y, Brown DN, da Silva EM, Pei X, Linkov I, Terraf P, Misyura M, Ceyhan-Birsoy O, Ladanyi M, Berger M, Pareja F, Stadler Z, Offit K, Riaz N, Park W, Chou J, Capanu M, Koehler M, Rosen E, O'Reilly EM, and Reis-Filho JS
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- Male, Humans, BRCA2 Protein genetics, BRCA1 Protein genetics, Germ-Line Mutation, Genetic Predisposition to Disease, Homologous Recombination, Genomics, Pancreatic Neoplasms, Carcinoma, Acinar Cell genetics, Pancreatic Neoplasms genetics
- Abstract
Purpose: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features., Methods: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed., Results: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD., Conclusion: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA -related malignancies.
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- 2023
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13. Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?
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Yu J, da Silva EM, La HS, Clark BZ, Fine JL, Carter GJ, Villatoro TM, Soong TR, Lee AV, Oesterreich S, Basili T, Blanco-Heredia J, Selenica P, Ye Q, Da Cruz Paula A, Dopeso H, Gazzo A, Marra A, Pareja F, Reis-Filho JS, and Bhargava R
- Abstract
This study describes "lobular-like invasive mammary carcinomas" (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management., (© 2023. The Author(s).)
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- 2023
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14. The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers.
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De Mattos-Arruda L, Cortes J, Blanco-Heredia J, Tiezzi DG, Villacampa G, Gonçalves-Ribeiro S, Paré L, Souza CA, Ortega V, Sammut SJ, Cusco P, Fasani R, Chin SF, Perez-Garcia J, Dienstmann R, Nuciforo P, Villagrasa P, Rubio IT, Prat A, and Caldas C
- Abstract
The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R
2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.- Published
- 2021
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15. Immune analysis of lymph nodes in relation to the presence or absence of tumor infiltrating lymphocytes in triple-negative breast cancer.
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Quintana Á, Peg V, Prat A, Moliné T, Villacampa G, Paré L, Galván P, Dientsmann R, Schmid P, Curigliano G, Muñoz-Couselo E, Perez-García J, Marti M, Blanco-Heredia J, Anjos CD, Vazquez M, De Mattos-Arruda L, and Cortés J
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- Adult, Aged, Case-Control Studies, Female, Follow-Up Studies, Gene Expression Profiling, Humans, Middle Aged, Prognosis, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms surgery, Biomarkers, Tumor genetics, Lymph Nodes immunology, Lymphocytes, Tumor-Infiltrating immunology, Triple Negative Breast Neoplasms immunology
- Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with unmet medical needs. Several studies have proved that high levels of tumor infiltrating lymphocytes (TILs) at diagnosis of TNBC confer better prognosis and patients respond better to specific chemotherapies. Nonetheless, current evidence suggests that only 15% of TNBC patients have very high levels of TILs, and another 15% lacks TILs. One possible reason to explain why patients have low TILs at diagnosis is that lymphocytes might be deactivated by an immune checkpoint in local lymph nodes, provoking their retention in there as they are unresponsive to other immune stimuli. We have identified 15 high TILs (≥50%) and 20 low TILs (≤5%) TNBC patients with localised tumour (T1c-T2N0M0) and compared the protein expression of five immune checkpoints in lymph nodes. We have also performed a customised 50-immune gene NanoString expression panel, the NanoString 360 Breast Cancer panel, and whole exome sequencing for mutation and neoantigen load analyses. In low TILs, we observed higher expression of CTLA-4 in local lymph nodes, which could explain why lymphocytes get retained in there and do not migrate to tumour. These patients have also higher neoantigen load and higher expression of B7.H3 and B7.H4 in the tumour. In high TILs, we observed more PD-L1+ tumour cells and more expanded humoral response. These results could provide a strategy to revert low tumour immune infiltration at diagnosis of TNBC, improving their prognosis., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: A.Q. received transportation and accommodation fees from MSD outside the submitted work. V.P. has received fees as consultant, participated in advisory boards or received travel grants from Sysmex, Roche, MSD, AstraZeneca and Genomic Health. A.P. has received personal fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; fees as a consultant from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD and Lilly; grants from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, MedSIR, Celgene, Astellas and Pzifer; is a member of the executive board of Reveal Genomics, SL, Beast International Group (BIG) and SOLTI cooperative group; and in the patronage committee of SOLTI Foundation and Actitud Frente al Cáncer Foundation. R.D. has declared advisory role for Roche, Boehringer Ingelheim, has received a speaker's fee from Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme, and research grants from Merck and Pierre Fabre. P.S. has received personal fees and fees as a consultant from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma and Roche; grants from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex and Roche. C.G. reports grants from Roche and Pfizer; and received personal fees from Daichii Sankyo, MSD, Astra Zeneca, outside the submitted work. J.P-G. has received fees as a consultant from Roche and Eli Lilly; and travel and accommodation expenses from Roche. E.M-C. has received travel and accommodation fees from BMS and MSD; personal fees and fees as a consultant from Novartis, Roche, BMS, MSD, Pier Fabre and Sanofi. L.M-A. has received consultancy from Roche; received an educational grant and travel from BMS; holds a research collaboration with NanoString Technologies; and received grants to the Institution from Grifols, Gilead, MSD, Jansen and AbbVie. J.C. has received fees as a consultant from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko; personal fees from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD, Daiichi Sankyo; research funding from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, MSD, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London, Seagen; and owns stock, patents and intellectual property from MedSIR. T.M., G.V., L.P., P.G., M.M., J.B.-H., C.A. and M.V. declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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16. Adherence to a Supplemented Mediterranean Diet Drives Changes in the Gut Microbiota of HIV-1-Infected Individuals.
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Pastor-Ibáñez R, Blanco-Heredia J, Etcheverry F, Sánchez-Palomino S, Díez-Fuertes F, Casas R, Navarrete-Muñoz MÁ, Castro-Barquero S, Lucero C, Fernández I, Leal L, Benito JM, Noguera-Julian M, Paredes R, Rallón N, Estruch R, Torrents D, and García F
- Subjects
- Adult, Bacterial Translocation, Bifidobacterium, Biomarkers blood, Female, Humans, Inflammation blood, Inflammation drug therapy, Lipids blood, Male, Middle Aged, Nuts, Olive Oil, Patient Compliance, Succinivibrionaceae, T-Lymphocyte Subsets, Diet, Mediterranean, Gastrointestinal Microbiome drug effects, HIV Infections diet therapy, HIV-1
- Abstract
Objective: The health effects of a supplemented Mediterranean diet (SMD) with extra-virgin olive oil (EVOO) and nuts are well documented in non-HIV-infected individuals. We hypothesised that the benefits of an SMD could be mediated by changes in the gut microbiota, even in those with an altered intestinal microbiota such as people living with HIV., Design: Individuals living with HIV ( n = 102) were randomised to receive an SMD with 50 g/day of EVOO and 30 g/day of walnuts (SMD group) or continue with their regular diet (control group) for 12 weeks., Methods: Adherence to the Mediterranean diet was assessed using the validated 14-item MD-Adherence-Screener (MEDAS) from the PREDIMED study. A sub-study classifying the participants according to their MEDAS scores was performed., Results: The lipid profile was improved in the SMD group vs. that in the control group (delta-total cholesterol and delta-B-lipoprotein). The immune activation (CD4+HLADR+CD38+ and CD8+HLADR+CD38+ cells) and IFN-γ-producing T-cells significantly decreased at week 12 compared to the baseline in the SMD group but not in the control group. The gut microbiota in those from the high-adherence group presented significantly high diversity and richness at the end of the intervention. Succinivibrio and Bifidobacterium abundances were influenced by the adherence to the MD and significantly correlated with Treg cells., Conclusion: The Mediterranean diet improved metabolic parameters, immune activation, Treg function, and the gut microbiota composition in HIV-1-infected individuals. Further, Mediterranean diet increased the Bifidobacterium abundances after the intervention, and it was associated to a beneficial profile.
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- 2021
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17. New emerging targets in cancer immunotherapy: the role of neoantigens.
- Author
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De Mattos-Arruda L, Blanco-Heredia J, Aguilar-Gurrieri C, Carrillo J, and Blanco J
- Subjects
- Antigens, Neoplasm immunology, Cancer Vaccines administration & dosage, Cancer Vaccines immunology, Humans, Immunotherapy, Adoptive, Molecular Targeted Therapy, Neoplasms immunology, Immunotherapy methods, Neoplasms therapy
- Abstract
The success of cancer therapies with immune checkpoint inhibitors is transforming the treatment of patients with cancer and fostering cancer research. Therapies that target immune checkpoint inhibitors have shown unprecedented rates of durable long-lasting responses in patients with various cancer types, but only in a fraction of patients. Thus, novel approaches are needed to make immunotherapy more precise and also less toxic. The advances of next-generation sequencing technologies have allowed fast detection of somatic mutations in genes present in the exome of an individual tumour. Targeting neoantigens, the mutated peptides expressed only by tumour cells, may enable antitumour T-cell responses and tumour destruction without causing harm to healthy tissues. Currently, neoantigens can be identified in tumour clinical samples by using genomic-based computational tools. The two main treatment modalities targeting neoantigens that have been investigated in clinical trials are personalised vaccines and tumour infiltrating lymphocytes-based adoptive T-cell therapy. In this mini review, we discuss the promises and challenges for using neoantigens as emergent targets to personalise and guide cancer immunotherapy in a broader set of cancers., Competing Interests: Competing interests: LDM-A has received honoraria for participation in a speaker’s bureau/ consultancy from Roche. JBH is CEO and cofounder and JC is CSO and cofounder of AlbaJuna Therapeutics., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)
- Published
- 2020
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18. Correction: Identification of Immunogenic Cytotoxic T Lymphocyte Epitopes Containing Drug Resistance Mutations in Antiretroviral Treatment-Naïve HIV-Infected Individuals.
- Author
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Blanco-Heredia J, Lecanda A, Valenzuela-Ponce H, Brander C, Ávila-Ríos S, and Reyes-Terán G
- Published
- 2016
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19. Identification of Immunogenic Cytotoxic T Lymphocyte Epitopes Containing Drug Resistance Mutations in Antiretroviral Treatment-Naïve HIV-Infected Individuals.
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Blanco-Heredia J, Lecanda A, Valenzuela-Ponce H, Brander C, Ávila-Ríos S, and Reyes-Terán G
- Subjects
- AIDS Vaccines immunology, Anti-Retroviral Agents therapeutic use, Enzyme-Linked Immunospot Assay, High-Throughput Nucleotide Sequencing, Humans, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance genetics, Epitopes, T-Lymphocyte genetics, HIV Infections genetics, HIV Infections immunology
- Abstract
Background: Therapeutic HIV vaccines may prove helpful to intensify antiretroviral treatment (ART) efficacy and may be an integral part of future cure strategies., Methods: We examined IFN-gamma ELISpot responses to a panel of 218 HIV clade B consensus-based HIV protease-reverse transcriptase peptides, designed to mimic previously described and predicted cytotoxic T lymphocyte epitopes overlapping drug resistance (DR) positions, that either included the consensus sequence or the DR variant sequence, in 49 ART-naïve HIV-infected individuals. Next generation sequencing was used to assess the presence of minority DR variants in circulating viral populations., Results: Although a wide spectrum of differential magnitudes of response to DR vs. WT peptide pairs was observed, responses to DR peptides were frequent and strong in the study cohort. No difference between the median magnitudes of response to DR vs. WT peptides was observed. Interestingly, of the 22 peptides that were recognized by >15% of the participants, two-thirds (64%) corresponded to DR peptides. When analysing responses per peptide pair per individual, responses to only WT (median 4 pairs/individual) or DR (median 6 pairs/individual) were more common than responses to both WT and DR (median 2 pairs/individual; p<0.001). While the presence of ELISpot responses to WT peptides was frequently associated with the presence of the corresponding peptide sequence in the patient's virus (mean 68% of cases), responses to DR peptides were generally not associated with the presence of DR mutations in the viral population, even at low frequencies (mean 1.4% of cases; p = 0.0002)., Conclusions: Our data suggests that DR peptides are frequently immunogenic and raises the potential benefit of broadening the antigens included in a therapeutic vaccine approach to immunogenic epitopes containing common DR sequences. Further studies are needed to assess the quality of responses elicited by DR peptides.
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- 2016
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20. Unique features of HLA-mediated HIV evolution in a Mexican cohort: a comparative study.
- Author
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Avila-Rios S, Ormsby CE, Carlson JM, Valenzuela-Ponce H, Blanco-Heredia J, Garrido-Rodriguez D, Garcia-Morales C, Heckerman D, Brumme ZL, Mallal S, John M, Espinosa E, and Reyes-Teran G
- Subjects
- Cohort Studies, Evolution, Molecular, Female, Gene Frequency, HIV Infections epidemiology, HIV-1 genetics, HLA Antigens genetics, Humans, Male, Mexico epidemiology, Adaptation, Biological, HIV Infections virology, HIV Protease genetics, HIV Reverse Transcriptase genetics, HIV-1 immunology, HLA Antigens immunology, Selection, Genetic
- Abstract
Background: Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level. However, it is not known whether characteristic HLA frequency distributions in different populations have resulted in additional unique footprints., Methods: The phylogenetic dependency network model was applied to assess HLA-mediated evolution in datasets of HIV pol sequences from free plasma viruses and peripheral blood mononuclear cell (PBMC)-integrated proviruses in an immunogenetically unique cohort of Mexican individuals. Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA., Results: Forty three different HLA-HIV codon associations representing 30 HLA-HIV codon pairs were observed in the Mexican cohort (q < 0.2). Strikingly, 23 (53%) of these associations differed from those observed in the well-powered IHAC cohort, strongly suggesting the existence of unique characteristics in HLA-mediated HIV evolution in the Mexican cohort. Furthermore, 17 of the 23 novel associations involved HLA alleles whose frequencies were not significantly different from those in IHAC, suggesting that their detection was not due to increased statistical power but to differences in patterns of epitope targeting. Interestingly, the consensus differed in four positions between the two cohorts and three of these positions could be explained by HLA-associated selection. Additionally, different HLA-HIV codon associations were seen when comparing HLA-mediated selection in plasma viruses and PBMC archived proviruses at the population level, with a significantly lower number of associations in the proviral dataset., Conclusion: Our data support universal HLA-mediated HIV evolution at the population level, resulting in detectable HLA-associated footprints in the circulating virus. However, it also strongly suggests that unique genetic backgrounds in different HIV-infected populations may influence HIV evolution in a particular direction as particular HLA-HIV codon associations are determined by specific HLA frequency distributions. Our analysis also suggests a dynamic HLA-associated evolution in HIV with fewer HLA-HIV codon associations observed in the proviral compartment, which is likely enriched in early archived HIV sequences, compared to the plasma virus compartment. These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.
- Published
- 2009
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